Rilpivirine, which is chemically known as 4-{[4-({4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino) pyrimidin-2-yl]amino}benzonitrile, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and exhibits human immunodeficiency virus (HIV) replication inhibiting properties. Rilpivirine is used as its hydrochloride salt in the anti-HIV formulations.

Conventionally, various processes followed for the synthesis of Rilpivirine hydrochloride (I), generally involve preparation of the key intermediate, (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II).

WO 03/016306 first disclosed the synthesis of Rilpivirine involving different routes for synthesis of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine. The first route involved protection of the amino group of 4-bromo-2,6-dimethylphenylamine by converting to N,N-dimethylmethanimidamide, followed by formylation involving n-butyl lithium and dimethylformamide. The resulting formyl derivative was treated with diethyl(cyanomethyl) phosphonate to give the cyanoethenyl compound which was deprotected using zinc chloride to yield the cyanoethenylphenylamine intermediate having an undisclosed E/Z ratio. This route involved an elaborate sequence of synthesis comprising protection of amine by its conversion into imide, use of a highly moisture sensitive and pyrophoric base such as butyl lithium and a low yielding formylation reaction. All these factors made the process highly unviable on industrial scale.
The second route disclosed in WO 03/016306 employed 4-iodo-2,6-dimethylphenylamine as a starting material for synthesis of cyanoethenylphenylamine intermediate, which involved reaction of the dimethylphenylamine derivative with acrylonitrile for at least 12 hours at 130° C. in presence of sodium acetate and a heterogeneous catalyst such as palladium on carbon. Isolation of the desired compound involved solvent treatment with multiple solvents followed by evaporation. This route also does not give any details of the E/Z ratio of the unsaturated intermediate product. Although this route avoids use of phosphine ligands but lengthy reaction time and problem of availability of pure halo-phenylamine derivatives coupled with moderate yields hampers the commercial usefulness of this route.
The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6-dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2-methylphenyl)phosphine and N,N-diethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2-cyanoethenyl)-2,6-dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio.
Although the E/Z isomer ratio for the cyanoethenyl derivative obtained from these routes is not specifically disclosed in the patent, however, reproducibility of the abovementioned reactions were found to provide an E/Z ratio between 70/30 and 80/20.
Various other methods have also been reported in the literature for introduction of the cyanoethenyl group in Rilpivirine. The Journal of Medicinal Chemistry (2005), 48, 2072-79 discloses Wittig or Wadsworth-Emmons reaction of the corresponding aldehyde with cyanomethyl triphenylphosphonium chloride to provide a product having an E/Z isomer ratio of 80/20. An alternate method of Heck reaction comprising reaction of aryl bromide with acrylonitrile in presence of tri-o-tolylphosphine and palladium acetate gave the same compound with a higher E/Z isomer ratio of 90/10. The method required further purification in view of the presence of a significant proportion of the Z isomer in the unsaturated intermediate.
A similar method was disclosed in Organic Process Research and Development (2008), 12, 530-536. However, the E/Z ratio of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine was found to be 80/20, which was found to improve to 98/2 (E/Z) after the compound was converted to its hydrochloride salt utilizing ethanol and isopropanol mixture.
It would be evident from the foregoing that prior art methods are associated with the following drawbacks:                a) High proportion of Z isomer, which requires elaborate purification by utilizing column chromatographic techniques, crystallization, or successive treatment with multiple solvents, which decreases the overall yield,        b) Introduction of cyanoethenyl group to the formylated benzenamine derivatives involves a moisture sensitive reagent like n-butyl lithium, which is not preferred on industrial scale. Further, the method utilizes cyanomethyl phosphonate esters and is silent about the proportion of the Z isomer and the higher percentage of impurities which requires elaborate purification and ultimately lowers the yield,        c) Prior art routes involve use of phosphine ligands which are expensive, environmentally toxic for large scale operations,        d) Prior art methods utilize phase transfer catalysts such as tetrabutyl ammonium bromide in stoichiometric amounts and the reactions are carried out at very high temperatures of up to 140-150° C.        
Thus, there is a need to develop an improved, convenient and cost effective process for preparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) having Z-isomer less than 0.5%, without involving any purification and does not involve use of phosphine reagent and which subsequently provides Rilpivirine hydrochloride (I) conforming to regulatory specifications.
The present inventors have developed a process for stereoselective synthesis of the key Rilpivirine intermediate, (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II), comprising diazotization of 2,6-dimethyl-4-amino-1-carboxybenzyl phenylamine followed by treatment with alkali tetrafluoroborate to provide the tetrafluoroborate salt of the diazonium ion which is followed by reaction with acrylonitrile in presence of palladium (II) acetate and subsequent deprotection of the amino group with an acid followed by treatment with hydrochloric acid to give the desired E isomer of compound (II) having Z isomer content less than 0.5% and with a yield of 75-80%. The compound (II) was subsequently converted to Rilpivirine hydrochloride of formula (I) with Z isomer content less than 0.1%.